Friday, May 16, 2025

 

Scientists find the ‘meow-tation’ that gives cats their orange fur



A small deletion in a gene on the X-chromosome lies behind the fiery coats of ginger tabbies and the splotchy orange patches of calicos and tortoiseshell cats.


Kyushu University

Professor Hiroyuki Sasaki with a calico cat 

image: 

Professor Hiroyuki Sasaki, a geneticist at Kyushu University with a soft spot for cats, makes fast friends with one of the calico cats at a local shelter while on his hunt for the gene behind orange fur.

view more 

Credit: Hiroyuki Sasaki/Kyushu University




Fukuoka, Japan—From Tama, Japan’s most famous stationmaster calico cat, to the lasagna-loving, ginger Garfield, cats with orange fur are both cultural icons and beloved pets. But their distinctive color comes with a genetic twist—most orange tabbies are male, while calicos and tortoiseshells are nearly always female. This pattern points to an unknown “orange gene” on the X chromosome, but identifying this gene has eluded scientists for decades.

Now, researchers from Kyushu University, Japan, have found the X-linked mutation behind orange fur in house cats. This deletion mutation, a type of mutation where a section of DNA is missing, not only explains the peculiarity of ginger genetics, but also reveals an entirely new mechanism for promoting orange coloring in animals. The findings are confirmed by a second independent study by researchers at Stanford University, U.S., with both papers publishing simultaneously in Current Biology on May 15, 2025.

“Identifying the gene has been a longtime dream, so it’s a joy to have finally cracked it,” says Professor Hiroyuki Sasaki, lead author of the study, self-proclaimed cat-lover, and geneticist at Kyushu University’s Medical Institute of Bioregulation and the Institute for Advanced Study.

For over a century, scientists have suspected that the orange gene is located on the X chromosome. Male cats, with only one X chromosome, will have orange coats if they inherit the orange gene. Females, with two X chromosomes, need two copies of the gene to be fully orange, making them less common. If females inherit one orange and one black gene, they develop the patchy or mottled coats seen in calicos and tortoiseshells.

“These ginger and black patches form because, early in development, one X chromosome in each cell is randomly switched off,” explains Sasaki. “As cells divide, this creates areas with different active coat color genes, resulting in distinct patches. The effect is so visual that it has become the textbook example of X-chromosome inactivation, even though the responsible gene was unknown.”

Armed with funding from a successful crowdfunding campaign, Sasaki therefore set out to find the elusive gene.

His team analyzed DNA from 18 cats—10 with orange fur and 8 without—and found that all orange cats shared a specific deletion in the ARHGAP36 gene, while the non-orange cats did not. This pattern held true in 49 additional cats, including samples from an international cat genome database. They also found that in mice, cats, and humans, the ARHGAP36 gene is chemically marked for silencing during X chromosome inactivation, aligning perfectly with the long-standing hypothesis.

“This was such strong evidence that even at this stage, we were confident that ARHGAP36 was the orange gene,” says Sasaki.

Looking closer at the mutation, Sasaki found that the deletion lies in a non-coding region of ARHGAP36, so the protein itself remains unchanged.

“This is key,” he explains. “ARHGAP36 is essential for development, with many other roles in the body, so I had never imagined it could be the orange gene. Mutations to the protein structure would likely be harmful to the cat.”

Instead, Sasaki’s team suspected the mutation altered the gene’s activity. With help from local vets, they examined skin tissue from four calico cats and found that ARHGAP36 was much more active in melanocytes—the pigment-producing cells found in skin—in tissue taken from orange patches compared to tissue from black or white patches.

“This suggests that when present, this section of DNA normally suppresses ARHGAP36 activity,” says Sasaki. “When missing, ARHGAP36 stays active.”

Further analysis showed that high ARHGAP36 activity is linked to reduced activity in many genes involved in melanogenesis, the process that produces pigment in skin and hair. Through a not yet known mechanism, the team believes this shift may steer pigment production from dark eumelanin to lighter pheomelanin, creating orange fur.

Since ARHGAP36 is active in many areas of the body, including in areas of the brain and hormonal glands, it’s possible that the orange variant may cause shifts in gene activity elsewhere, influencing more than just coat color.

“For example, many cat owners swear by the idea that different coat colors and patterns are linked with different personalities,” laughs Sasaki. “There’s no scientific evidence for this yet, but it’s an intriguing idea and one I’d love to explore further.”

Sasaki has other big plans ahead, including using cat cell cultures to decipher the molecular function of ARHGAP36. Since the gene also exists in humans and is linked to conditions like skin cancer and hair loss, the findings could have surprising medical relevance.

He’s also curious about the orange gene’s origins, such as where and when the mutation happened. “One idea is to study ancient Egyptian cat paintings—or even to test DNA from mummified cats—to see if any cats back then were orange,” he says. “It’s ambitious, but I’m excited to try.”


Calico cats have X chromosomes that have two variants of the gene ARHGAP36. In orange patches of fur, the active chromosome (red) contains a deletion mutation in ARHGAP36, which increases its expression and reduces the activity of melanogenesis genes. This leads to higher levels of pheomelanin, resulting in ginger fur. In black patches of fur, the active chromosome (red) does not contain the deletion, and ARHGAP36 is suppressed. The activity of melanogenesis genes remains high, and eumelanin is produced, resulting in black fur.

Calico cats (left) and tortoiseshell cats (right) are the classic example of X chromosome inactivation, where either an orange color or a black color variant of a gene on the X chromosome is active in skin cells, resulting in orange and black patches.

Credit

Hiroyuki Sasaki/Kyushu University

For more information about this research, see “A deletion at the X-linked ARHGAP36 gene locus is associated with the orange coloration of tortoiseshell and calico cats” Hidehiro Toh, Wan Kin Au Yeung, Motoko Unoki, Yuki Matsumoto, Yuka Miki, Yumiko Matsumura, Yoshihiro Baba, Takashi Sado, Yasukazu Nakamura, Miho Matsuda, Hiroyuki Sasaki, Current Biologyhttps://doi.org/10.1016/j.cub.2025.03.075

About Kyushu University 

Founded in 1911, Kyushu University is one of Japan's leading research-oriented institutes of higher education, consistently ranking as one of the top ten Japanese universities in the Times Higher Education World University Rankings and the QS World Rankings. The university is one of the seven national universities in Japan, located in Fukuoka, on the island of Kyushu—the most southwestern of Japan’s four main islands with a population and land size slightly larger than Belgium. Kyushu U’s multiple campuses—home to around 19,000 students and 8000 faculty and staff—are located around Fukuoka City, a coastal metropolis that is frequently ranked among the world's most livable cities and historically known as Japan's gateway to Asia. Through its VISION 2030, Kyushu U will “drive social change with integrative knowledge.” By fusing the spectrum of knowledge, from the humanities and arts to engineering and medical sciences, Kyushu U will strengthen its research in the key areas of decarbonization, medicine and health, and environment and food, to tackle society’s most pressing issues.

 

Understanding carbon traps



Physical probing of a promising material shows exactly how it locks CO₂ into place



Helmholtz-Zentrum Dresden-Rossendorf

Artistic representation of CO2 capture from a moisture-laden gas stream using CALF-20, a zinc-based metal-organic framework. 

image: 

Artistic representation of CO2 capture from a moisture-laden gas stream using CALF-20, a zinc-based metal-organic framework. Also shown: The decay of positronium, which is used to probing the void of the MOF. In this process, an electron and a positron annihilate each other to produce characteristic gamma rays which can be detected.

view more 

Credit: B. Schröder/HZDR





As industries seek innovative solutions for carbon capture, scientists have turned to advanced materials that efficiently trap and store carbon dioxide (CO₂) from industrial emissions. A recent study of a team from the Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden University of Technology (TUD), and Maria Curie-SkÅ‚odowska University in Lublin (Poland) sheds light on the gas adsorption physics of so-called Calgary Framework 20 (CALF-20), a zinc-based metal-organic framework (MOF). While applying a combination of advanced techniques, the scientists reveal the material’s unique adaptability under varying conditions, as they report in the journal Small (DOI: 10.1002/smll.202500544). The research highlights how CALF-20 efficiently captures CO₂ while resisting interference from water – a common issue in carbon capture materials.

CO₂ capture technologies rely on materials that can selectively trap the greenhouse gas from gas streams while minimizing energy consumption. Traditional adsorbents, such as activated carbons and zeolites, often suffer from high-energy demands or poor selectivity in humid environments. In contrast, CALF-20 stands out due to its high CO₂ uptake and its mild heat of adsorption and regeneration. It maintains a high selectivity by preferentially adsorbing CO₂ over water in moderately humid conditions. CALF-20 captures CO₂ more effectively and absorbs less water in such conditions, when compared to other widely studied similar compounds. All those MOFs are highly porous and made of metal-oxygen clusters, which are connected in a structured manner by pillars of organic chemicals. This three-dimensional arrangement leads to networks of cavities reminiscent of the pores of a kitchen sponge.

“In this study, we employed a multifaceted approach to investigate CALF-20’s CO₂ adsorption behavior. Using a combination of positron annihilation lifetime spectroscopy (PALS), in situ powder X-ray diffraction (PXRD), as well as gas adsorption experiments, we were able to visualize the interaction between CO₂ molecules and the material’s internal structure under different temperatures and humidity levels. These insights provide important information for optimizing CO₂ capture technologies in real-world industrial settings”, explains Dr. Ahmed Attallah from the Institute of Radiation Physics at HZDR.

A deep dive into adsorption mechanisms

“PALS plays a critical role in analyzing how gases interact with porous materials. This technique measures the lifetime of positronium, a bound state of an electron and a positron, which is sensitive to local free volumes. In porous materials like CALF-20, positronium lifetimes indicate empty spaces, their size, and how they change when gas molecules start to fill the pores”, Prof. RadosÅ‚aw Zaleski from the Maria Curie-SkÅ‚odowska University Lublin says.

Through PALS, researchers observed that CO₂ initially gathers at the center of CALF-20’s nanopores, forming a structured arrangement before adhering to the pore walls. This progression correlates with increasing CO₂ pressure, confirming that PALS can track molecular adsorption steps in real time. The method also revealed that even after CO₂ fills the pores, small free volumes persist, which may be critical for enhancing adsorption efficiency.

PALS was particularly useful in distinguishing how CO₂ and water interact within the material. Under humid conditions, PALS data showed that water forms isolated clusters at low humidity, but at higher humidity levels, it forms interconnected networks. “These structural changes affect pore accessibility, yet CALF-20 maintains its significant CO₂ adsorption capacity at a relative humidity below 40 per cent. Conventional gas adsorption methods alone would struggle to resolve these fine structural variations, demonstrating the unique value of PALS in analyzing dynamic gas-material interactions”, TUD’s Prof. Stefan Kaskel resumes.

The impact of humidity: A key challenge in CO₂ capture

In industrial applications, CO₂ is rarely captured from dry gas streams – moisture is almost always present. This poses a challenge for many materials, as water molecules often compete with CO₂ for adsorption sites, reducing efficiency.

Through in situ humidity-controlled experiments, the team discovered that CALF-20 maintains a robust CO₂ adsorption performance even in the presence of water, where the level of relative humidity defines this robustness. At low humidity, water molecules remain isolated within the framework. This network formation alters the material’s free volume, but CO₂ still finds available adsorption sites, demonstrating CALF-20’s resilience under humid conditions. At increasingly higher humidity levels, they form interconnected hydrogen-bonded networks, allowing water uptake to dominate.

By integrating PALS with other characterization techniques, this study provides a comprehensive understanding of how CALF-20 captures CO₂ under diverse environmental conditions. The results suggest that CALF-20 could serve as a scalable and energy-efficient solution for industrial CO₂ capture, particularly in settings where humidity poses a challenge. Developed by researchers at the University of Calgary, CALF-20 has already been scaled up to multi-kilogram production, making it a strong candidate for real-world applications

The implications extend beyond fundamental science – these insights could pave the way for optimizing next-generation MOFs for large-scale deployment in carbon capture and storage (CCS) applications. Further research will focus on long-term stability and process integration, moving closer to the implementation of CALF-20 in industrial CO₂ mitigation strategies.

The study was supported by DFG (Deutsche Forschungsgemeinschaft) under contract 464857745 (AT 289/1-1 and KA1698/41-1).

Publication:
A. G. Attallah, V. Bon, E. Hirschmann, M. Butterling, A. Wagner, R. Zaleski, S. Kaskel, Uncovering the dynamic CO2 gas uptake behavior of CALF-20 (Zn) under varying conditions via positronium lifetime analysis, in Small, 2025 (DOI: 10.1002/smll.202500544)

More information:

The Helmholtz-Zentrum Dresden-Rossendorf (HZDR) performs – as an independent German research center – research in the fields of energy, health, and matter. We focus on answering the following questions:

  • How can energy and resources be utilized in an efficient, safe, and sustainable way?
  • How can malignant tumors be more precisely visualized, characterized, and more effectively treated?
  • How do matter and materials behave under the influence of strong fields and in smallest dimensions?

To help answer these research questions, HZDR operates large-scale facilities, which are also used by visiting researchers: the Ion Beam Center, the Dresden High Magnetic Field Laboratory and the ELBE Center for High-Power Radiation Sources.
HZDR is a member of the Helmholtz Association and has six sites (Dresden, Freiberg, Görlitz, Grenoble, Leipzig, Schenefeld near Hamburg) with almost 1,500 members of staff, of whom about 680 are scientists, including 200 Ph.D. candidates.

 

First all-oral treatment for a rare but deadly strain of sleeping sickness now available and being used to treat patients in endemic countries in Africa


A handful of patients in Ethiopia, Malawi, Tanzania, Zambia, and Zimbabwe, as well as foreign travellers, have now been treated with a medicine that is revolutionizing care for patients with rhodesiense sleeping sickness



Drugs for Neglected Diseases Initiative




GENEVA / LILONGWE – 13 MAY 2025 – The first all-oral treatment for Trypanosoma brucei (T.b.) rhodesiense sleeping sickness, an acute form of the disease, is now available free of charge to patients in specialized treatment centres in Ethiopia, Malawi, Tanzania, Zambia, and Zimbabwe.

Ministries of Health in several African countries have approved the use of Fexinidazole Winthrop for T.b. rhodesiense sleeping sickness treatment.

Until now, the only treatment for the advanced stage of the disease involved a toxic intravenous drug that required hospitalization. Today, with this breakthrough, we have a safe and simple oral treatment that can be taken at home with minimal observation, revolutionizing care for patients. The authorization of Fexinidazole Winthrop in Malawi and several other African countries is a testament to the dedication and hard work of African doctors, clinicians, healthcare staff, and communities who contributed to its development,’ said Dr Westain Nyirenda, principal investigator of the clinical trials for Fexinidazole Winthrop in Malawi.

The clinical trials that led to Fexinidazole Winthrop’s approval were sponsored by the not-for-profit medical research organization Drugs for Neglected Diseases initiative (DNDi).

Sleeping sickness, or human African trypanosomiasis (HAT), is a parasitic disease transmitted by the bite of tsetse flies. It causes neuropsychiatric symptoms, including a debilitating disruption of sleep patterns and ultimately coma and death. It is almost always fatal if not treated. The T.b. rhodesiense form of the disease, which occurs in East and Southern Africa, progresses more rapidly than the T.b. gambiense form, which is endemic to Western and Central Africa.

Fexinidazole Winthrop was developed through an innovative partnership that brought together Sanofi, DNDi, national sleeping programmes, and local communities. The European Medicines Agency issued a positive scientific opinion for treatment of T.b. gambiense with Fexinidazole Winthrop in 2018. For T.b. rhodesiense sleeping sickness, DNDi led a Phase II/III clinical trial in Malawi and Uganda supported by a consortium of partners known as HAT-r-ACC that showed the treatment is a better alternative to existing drugs. 

The results led the European Medicines Agency to issue a positive scientific opinion in December 2023. Following this decision, a regulatory approval was given in May 2025 by the regulatory authorities of the Democratic Republic of the Congo and subsequently, Malawi approved its use in December 2024. In June 2024, the World Health Organization (WHO) included it as the first-choice treatment for rhodesiense sleeping sickness in its treatment guidelines. Since the beginning of 2025, importation and distribution of the drug have been approved in the five African countries listed above and received shipments from WHO. Several patients have already received this life-saving treatment in Malawi, Zambia, and Zimbabwe.

Deadly outbreaks of rhodesiense sleeping sickness still occur, most recently in Malawi from 2019 to 2021. A localized rhodesiense outbreak in Ethiopia in 2022 – the first in 30 years – has been linked to climate and environmental changes that bring humans and animals such as cattle in closer proximity to the tsetse flies that carry the disease. Safari tourists from Europe and the US visiting the region have also fallen ill with this strain of sleeping sickness and have received Fexinidazole Winthrop under compassionate use protocols in Austria, Denmark, Poland, and the United States.

With climate and environmental changes increasing the risk of future rhodesiense outbreaks, we are now prepared to meet these challenges head-on with all-oral treatments, which will save lives and ease the burden on our healthcare systems in Africa,’ said Dr Junior Matangila, Head of DNDi’s sleeping sickness programme. ‘This is important, as it will be difficult to interrupt transmission of the rhodesiense form of sleeping sickness because it has an animal reservoir. On the other hand, as the reservoir of gambiense sleeping sickness is essentially human, interruption of transmission is an attainable goal. So far, eight countries have eliminated gambiense sleeping sickness as a public health problem, the latest being Guinea earlier this year.’

Fexinidazole Winthrop is recommended for adults and children aged six years or older and weighing at least 20 kg who have been diagnosed with either first-stage (haemolymphatic) or second-stage (meningoencephalitic) rhodesiense sleeping sickness in addition to the treatment of gambiense sleeping sickness approved in 2018. The all-oral treatment is donated to the WHO by Foundation S, Sanofi’s philanthropic organization, and delivered to Africa by the Médecins Sans Frontières Logistique supply centre.

We are thrilled to see the access and use of Fexinidazole Winthrop as the first fully oral treatment to treat rhodesiense sleeping sickness in Africa. This milestone underscores Sanofi's unwavering long-term commitment to addressing neglected tropical diseases challenges and improving patient outcomes. Through Foundation S, we are dedicated to providing innovative treatments to those who need them most, ensuring that no patient is left behind. This approval is a testament to the power of collaboration and the impact we can achieve together, contributing further to eliminate sleeping sickness,’ said Philippe Neau, Head of the Neglected Tropical Diseases (NTDs) Programme at Foundation S, the Sanofi collective.

The DNDi clinical trial for T.b. rhodesiense sleeping sickness was conducted by the HAT-r-ACC Consortium, with funding from the European and Developing Countries Clinical Trials Partnership (EDCTP2) programme supported by the European Union (through the grant RIA2017NCT-1846); Fundação para a Ciência e a Tecnologia, Portugal; the Swiss Agency for Development and Cooperation (SDC); Médecins Sans Frontières; UK International Development; and other private foundations and individuals.

ENDS.

 

About DNDi

The Drugs for Neglected Diseases initiative (DNDi) is a not-for-profit medical research organization that discovers, develops, and delivers safe, effective, and affordable treatments for neglected people. DNDi and its partners have developed three safe, effective, and accessible treatments for both forms of sleeping sickness, including the combination NECT in 2009; the first all-oral treatment Fexinidazole Winthrop for the gambiense form of sleeping sickness in 2018; and Fexinidazole Winthrop for the rhodesiense form of the disease in 2023. DNDi and Sanofi are also developing a promising, single-dose oral treatment for sleeping sickness called acoziborole that opens the door to the elimination of the disease in Africa. Since its creation in 2003, DNDi has joined with public and private partners across the globe to deliver 13 new treatments, saving millions of lives. dndi.org

About HAT-r-ACC

The HAT-r-ACC consortium brings together a broad range of partners with expertise in sleeping sickness and capacity building in remote healthcare settings. This research, training, and community engagement experience were essential to running the clinical trial in remote settings with a very small target population. The consortium partners include the Malawi Ministry of Health, the Uganda National Health Research Organisation, the Makerere University of Uganda, Epicentre (MSF) in France, the Lisbon Institute of Hygiene and Tropical Medicine in Portugal, the Institut de Recherche pour le Développement in France, the Swiss Tropical and Public Health Institute (Swiss TPH), and the WHO.